Editorial: Trimethoprim-sulfamethoxazole (TMP-SMZ)--better late than never.
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Primary rat hepatocyte suspension cultures (approximately 2 X 10(6) cells) exposed to solubilized 2,3,4-trimethylpentane at concentrations ranging from 7.9 to 31.5 mM under two different culture conditions resulted in a linear dose response, as determined by lactate dehydrogenase leakage and viability data. A significant increase in the 2,3,4-trimethylpentane effective concentration 50 for primary hepatocytes occurred when exposures were implemented in medium containing 0.05% albumin. The effective concentration 50 for hepatocytes exposed to 2,3,4-trimethylpentane in medium lacking and containing albumin were 17.1 and 20.7 mM, respectively. Metabolite analysis by gas chromatography-mass spectrometry of supernatant (lacking or containing albumin) and cell extracts from hepatocyte cultures exposed to 2,3,4-trimethylpentane for 4 h indicated the presence of three metabolites: 2,3,4-trimethyl-1-pentanol, 2,3,4-trimethyl-2-pentanol, 2,3,4-trimethyl-2-pentanol, and 2,3,4-trimethyl-1-pentanoic acid. Electron microscopic examination of 2,3,4-trimethylpentane-exposed primary hepatocytes indicated ultrastructural changes which included abnormal condensed chromatin association with the nuclear membrane, swollen mitochondria, increased amounts of cytoplasmic lipid, significant loss of microvilli from the cell surface, increased vacuolation, and increased numbers of peroxisomes. Although these changes were observed under both culture conditions, they were more severe in cultures lacking albumin. This study indicates that primary hepatocyte suspension cultures provide a useful system for rapidly identifying liver metabolites of selected test compounds of interest.
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Morphological and numerical changes in the epidermal melanocytes of black C57BL mice after phototoxic drug administration followed by ultraviolet A irradiation were studied to compare the effects of photochemotherapy on the epidermal melanocytes using 8-methoxypsoralen and trimethylpsoralen. One hour after intraperitoneal injection of the phototoxic drugs, 1.5 mg/kg in the small dose group and 6.0 mg/kg in the large dose group, the mice were exposed to UVA irradiation. This procedure was performed twice a week for 8 weeks at the small dose group and for 5 weeks in the large dose group. Skin biopsies were taken before irradiation in both groups, and follow up biopsies were done at each week. The number and size of the melanocytes were observed in a split-DOPA preparation. In the drug treated groups, there was an increase in the size of the perikaryon, and the number, length, width, and arborization of dendrites. Such changes were more clearly seen in the group treated with trimethylpsoralen compared with the 8-methoxypsoralen treated group. Therefore, trimethylpsoralen is more effective than 8-methoxypsoralen in the increase of the perikaryon size, and the number, length, width, and arborization of dendrites of melanocytes in the intraperitoneal injection.
The potential impact on a variety of bioassay organisms when pulp-mill biosolids from a thermomechanical pulp mill (western Canada) were applied to a reference soil has been investigated in a laboratory setup. The current research assessed acute, chronic, and reproductive impacts using a battery of terrestrial and aquatic organisms. Terrestrial organisms were exposed to soil amended with different concentrations of biosolids, while aquatic organisms were used to assess the impact of biosolids' runoff into receiving waters. The former bioassays showed that an application rate of 20 tonneshectare(-1) (tha(-1)) "bone-dry" biosolids applied to reference soil produced no observable adverse impact on the terrestrial organisms. In the latter assays, undiluted (100%) and 50% diluted biosolids' runoff into receiving water had a detrimental impact on the aquatic organisms. However, concentrations not exceeding 25% (environmentally relevant concentrations) had neither an acute nor chronic impact compared to reference populations. The organisms' abilities to reproduce were also unaltered. While this study only examined the biosolids from one mill, there is the potential that land-application of characteristically well-defined pulp mill biosolids may constitute an acceptable way of disposing of pulp and paper mill biosolid residues. However, the biosolids coming from different mills, with differing processes, must be dealt with on a case-by-case situation. Each series of biosolids must be rigorously tested for toxicological impact in the laboratory under tightly controlled conditions. Subsequently, field experimentation must be conducted before definitive conclusions can be made.
The carriage rate of ampicillin-resistant Hemophilus influenzae type B in a chronic care facility was investigated. Up to 48% of the children carried this strain. Of interest was the finding of simulaneous carriage of ampicillin-resistant and ampicillin-sensitive HITB, a phenomenon which was detected by using both chocolate agar and chocolate agar containing 2 microgram/ml of ampicillin. A trial of sulfamethoxazole-trimethoprin successfully eradicated the ampicillin-sensitive HITB, but had no effect on the ampicillin-resistant HITB.
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We assessed the activity and safety of a biochemotherapy regimen in which courses of paclitaxel, methotrexate, and cisplatin were alternated with courses of 5-fluorouracil, alpha-interferon, and cisplatin in the treatment of refractory urothelial carcinoma. Forty patients were enrolled in the study. In the phase I portion, 15 patients were treated according to an escalating dosage regimen designed to determine the maximum tolerated dose. A total of 30 patients received treatment according to the maximum tolerated dose regimen: methotrexate (30 mg/m(2)) given iv on days 1 and 22; paclitaxel (175 mg/m(2)) given iv over 3 h on day 1; cisplatin (70 and 25 mg/m(2)) administered iv on days 1 and 22, respectively; 5-fluorouracil (400 mg/m(2)) given iv by continuous infusion daily for 5 days beginning on day 22; and alpha-interferon (4 mIU/m(2)) given SC daily for 5 days simultaneously with the 5-fluorouracil infusions. The regimen was repeated at 42-day intervals. The 40 treated patients had an overall response rate of 43%, a complete response rate of 18%, and a median survival time of 44 weeks. Most of the toxic effects were hematologic: Grade 4 neutropenia occurred in 30% of patients (12 patients) and Grade 3 thrombocytopenia in 20% (8 patients). Even though this alternating biochemotherapy regimen was active for patients with refractory urothelial carcinoma, its activity was not better than that of certain single cytotoxic agents. Furthermore, the complicated dosing schedule and toxic effects of the regimen precluded its routine use in the treatment of urothelial carcinoma.
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